Human and animal studies have demonstrated the role of oxidative stress in hypertension, and growing evidence points to oxidative mechanisms as pathologic mediators in hypertensive target organ damage. Both Angiotensin II (Ang U) and inhibition of nitric oxide (NO) generation can augment oxidative stress. The importance of NO in controlling human vascular tone has been demonstrated, and in human essential hypertension and hypercholesterolemia, impaired NO bioavailability may sensitize the vasculature to the cytotoxic effects of Ang H. Our preliminary studies demonstrated that nitric oxide synthase (NOS) inhibition by L-NAME synergistically increases damage to heart and kidneys caused by relatively small amounts of Ang II over a very rapid time frame (within 2 days). This observation suggests that under conditions of reduced nitric oxide bioavailability small transient increases in Ang II may result in abnormally high cellular damage. During the early phase (first 2 days) of L-NAME + Ang H coinfusion there was a surge in plasma aldosterone level, and a marked inflammatory response in kidneys and heart. Changes in gene expression obtained from DNA microarray analyses of kidney mRNA levels suggested several mechanisms to account for these changes. [unreadable] [unreadable] Specific Aims of this proposal are: (I) To determine the relationship of the surge in plasma aldosterone levels with the cardiac and renal injuries produced in the L-NAME + Ang II coinfusion model; (2) To determine the role of selected genes (osteopontin, gp9 1 phox and I 2-lipoxygenase) whose mRNA levels change in response to L-NAME + Ang II on the development of target organ damage in heart and kidneys; and (3) To determine the NOS isoform whose inhibition exacerbates the target organ damage caused by Ang II.